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Accumulating evidence suggests a role of FKBP5, a co-chaperone regulating the glucocorticoid receptor sensitivity, in the etiology of depression and anxiety disorders. Based on recent findings of altered amygdala activity following childhood adversity, the present study aimed at clarifying the impact of genetic variation in FKBP5 on threat-related neural activity and coupling as well as morphometric alterations in stress-sensitive brain systems. Functional magnetic resonance imaging during an emotional face-matching task was performed in 153 healthy young adults (66 males) from a high-risk community sample followed since birth. Voxel-based morphometry was applied to study structural alterations and DNA was genotyped for FKBP5 rs1360780. Childhood adversity was measured using retrospective self-report (Childhood Trauma Questionnaire) and by a standardized parent interview assessing childhood family adversity. Depression was assessed by the Beck Depression Inventory. There was a main effect of FKBP5 on the left amygdala, with T homozygotes showing the highest activity, largest volume and increased coupling with the left hippocampus and the orbitofrontal cortex (OFC). Moreover, amygdala-OFC coupling proved to be associated with depression in this genotype. In addition, our results support previous evidence of a gene-environment interaction on right amygdala activity with respect to retrospective assessment of childhood adversity, but clarify that this does not generalize to the prospective assessment. These findings indicated that activity in T homozygotes increased with the level of adversity, whereas the opposite pattern emerged in C homozygotes, with CT individuals being intermediate. The present results point to a functional involvement of FKBP5 in intermediate phenotypes associated with emotional processing, suggesting a possible mechanism for this gene in conferring susceptibility to stress-related disorders.
Conduct disorder (CD) causes high financial and social costs, not only in affected families but across society, with only moderately effective treatments so far. There is consensus that CD is likely caused by the convergence of many different factors, including genetic and adverse environmental factors. There is ample evidence of gene-environment interactions in the etiology of CD on a behavioral level regarding genetically sensitive designs and candidate gene-driven approaches, most prominently and consistently represented by MAOA. However, conclusive indications of causal GxE patterns are largely lacking. Inconsistent findings, lack of replication and methodological limitations remain a major challenge. Likewise, research addressing the identification of affected brain pathways which reflect plausible biological mechanisms underlying GxE is still very sparse. Future research will have to take multilevel approaches into account, which combine genetic, environmental, epigenetic, personality, neural and hormone perspectives. A better understanding of relevant GxE patterns in the etiology of CD might enable researchers to design customized treatment options (e.g. biofeedback interventions) for specific subgroups of patients.
Dimensional psychiatry
(2014)
A dimensional approach in psychiatry aims to identify core mechanisms of mental disorders across nosological boundaries.
We compared anticipation of reward between major psychiatric disorders, and investigated whether reward anticipation is impaired in several mental disorders and whether there is a common psychopathological correlate (negative mood) of such an impairment.
We used functional magnetic resonance imaging (fMRI) and a monetary incentive delay (MID) task to study the functional correlates of reward anticipation across major psychiatric disorders in 184 subjects, with the diagnoses of alcohol dependence (n = 26), schizophrenia (n = 44), major depressive disorder (MDD, n = 24), bipolar disorder (acute manic episode, n = 13), attention deficit/hyperactivity disorder (ADHD, n = 23), and healthy controls (n = 54). Subjects' individual Beck Depression Inventory-and State-Trait Anxiety Inventory-scores were correlated with clusters showing significant activation during reward anticipation.
During reward anticipation, we observed significant group differences in ventral striatal (VS) activation: patients with schizophrenia, alcohol dependence, and major depression showed significantly less ventral striatal activation compared to healthy controls. Depressive symptoms correlated with dysfunction in reward anticipation regardless of diagnostic entity. There was no significant correlation between anxiety symptoms and VS functional activation.
Our findings demonstrate a neurobiological dysfunction related to reward prediction that transcended disorder categories and was related to measures of depressed mood. The findings underline the potential of a dimensional approach in psychiatry and strengthen the hypothesis that neurobiological research in psychiatric disorders can be targeted at core mechanisms that are likely to be implicated in a range of clinical entities.
Mental health problems remain among the main generators of costs within and beyond the health care system. Psychotherapy, the tool of choice in their treatment, is qualified by social interaction, and cooperation within the therapist-patient-dyad. Research into the factors influencing therapy success to date is neither exhaustive nor conclusive. Among many others, the quality of the relationship between therapist and patient stands out regardless of the followed psychotherapy school. Emerging research points to a connection between interpersonal synchronization within the sessions and therapy outcome. Consequently, it can be considered significant for the shaping of this relationship. The framework of Embodied Cognition assumes bodily and neuronal correlates of thinking. Therefore, the present paper reviews investigations on interpersonal, non-verbal synchrony in two domains: firstly, studies on interpersonal synchrony in psychotherapy are reviewed (synchronization of movement). Secondly, findings on neurological correlates of interpersonal synchrony (assessed with EEG, fMRI, fNIRS) are summarized in a narrative manner. In addition, the question is asked whether interpersonal synchrony can be achieved voluntarily on an individual level. It is concluded that there might be mechanisms which could give more insights into therapy success, but as of yet remain uninvestigated. Further, the framework of embodied cognition applies more to the current body of evidence than classical cognitivist views. Nevertheless, deeper research into interpersonal physical and neurological processes utilizing the framework of Embodied Cognition emerges as a possible route of investigation on the road to lower drop-out rates, improved and quality-controlled therapeutic interventions, thereby significantly reducing healthcare costs.
Mental health problems remain among the main generators of costs within and beyond the health care system. Psychotherapy, the tool of choice in their treatment, is qualified by social interaction, and cooperation within the therapist-patient-dyad. Research into the factors influencing therapy success to date is neither exhaustive nor conclusive. Among many others, the quality of the relationship between therapist and patient stands out regardless of the followed psychotherapy school. Emerging research points to a connection between interpersonal synchronization within the sessions and therapy outcome. Consequently, it can be considered significant for the shaping of this relationship. The framework of Embodied Cognition assumes bodily and neuronal correlates of thinking. Therefore, the present paper reviews investigations on interpersonal, non-verbal synchrony in two domains: firstly, studies on interpersonal synchrony in psychotherapy are reviewed (synchronization of movement). Secondly, findings on neurological correlates of interpersonal synchrony (assessed with EEG, fMRI, fNIRS) are summarized in a narrative manner. In addition, the question is asked whether interpersonal synchrony can be achieved voluntarily on an individual level. It is concluded that there might be mechanisms which could give more insights into therapy success, but as of yet remain uninvestigated. Further, the framework of embodied cognition applies more to the current body of evidence than classical cognitivist views. Nevertheless, deeper research into interpersonal physical and neurological processes utilizing the framework of Embodied Cognition emerges as a possible route of investigation on the road to lower drop-out rates, improved and quality-controlled therapeutic interventions, thereby significantly reducing healthcare costs.
Conceptual knowledge about objects, people and events in the world is central to human cognition, underlying core cognitive abilities such as object recognition and use, and word comprehension. Previous research indicates that concepts consist of perceptual and motor features represented in modality-specific perceptual-motor brain regions. In addition, cross-modal convergence zones integrate modality-specific features into more abstract conceptual representations.
However, several questions remain open: First, to what extent does the retrieval of perceptual-motor features depend on the concurrent task? Second, how do modality-specific and cross-modal regions interact during conceptual knowledge retrieval? Third, which brain regions are causally relevant for conceptually-guided behavior? This thesis addresses these three key issues using functional magnetic resonance imaging (fMRI) and transcranial magnetic stimulation (TMS) in the healthy human brain.
Study 1 - an fMRI activation study - tested to what extent the retrieval of sound and action features of concepts, and the resulting engagement of auditory and somatomotor brain regions depend on the concurrent task. 40 healthy human participants performed three different tasks - lexical decision, sound judgment, and action judgment - on words with a high or low association to sounds and actions. We found that modality-specific regions selectively respond to task-relevant features: Auditory regions selectively responded to sound features during sound judgments, and somatomotor regions selectively responded to action features during action judgments. Unexpectedly, several regions (e.g. the left posterior parietal cortex; PPC) exhibited a task-dependent response to both sound and action features. We propose these regions to be "multimodal", and not "amodal", convergence zones which retain modality-specific information.
Study 2 - an fMRI connectivity study - investigated the functional interaction between modality-specific and multimodal areas during conceptual knowledge retrieval. Using the above fMRI data, we asked (1) whether modality-specific and multimodal regions are functionally coupled during sound and action feature retrieval, (2) whether their coupling depends on the task, (3) whether information flows bottom-up, top-down, or bidirectionally, and (4) whether their coupling is behaviorally relevant. We found that functional coupling between multimodal and modality-specific areas is task-dependent, bidirectional, and relevant for conceptually-guided behavior. Left PPC acted as a connectivity "switchboard" that flexibly adapted its coupling to task-relevant modality-specific nodes.
Hence, neuroimaging studies 1 and 2 suggested a key role of left PPC as a multimodal convergence zone for conceptual knowledge. However, as neuroimaging is correlational, it remained unknown whether left PPC plays a causal role as a multimodal conceptual hub. Therefore, study 3 - a TMS study - tested the causal relevance of left PPC for sound and action feature retrieval. We found that TMS over left PPC selectively impaired action judgments on low sound-low action words, as compared to sham stimulation. Computational simulations of the TMS-induced electrical field revealed that stronger stimulation of left PPC was associated with worse performance on action, but not sound, judgments. These results indicate that left PPC causally supports conceptual processing when action knowledge is task-relevant and cannot be compensated by sound knowledge. Our findings suggest that left PPC is specialized for action knowledge, challenging the view of left PPC as a multimodal conceptual hub.
Overall, our studies support "hybrid theories" which posit that conceptual processing involves both modality-specific perceptual-motor regions and cross-modal convergence zones. In our new model of the conceptual system, we propose conceptual processing to rely on a representational hierarchy from modality-specific to multimodal up to amodal brain regions. Crucially, this hierarchical system is flexible, with different regions and connections being engaged in a task-dependent fashion. Our model not only reconciles the seemingly opposing grounded cognition and amodal theories, it also incorporates task dependency of conceptually-related brain activity and connectivity, thereby resolving several current issues on the neural basis of conceptual knowledge retrieval.
Processing of reward is the basis of adaptive behavior of the human being. Neural correlates of reward processing seem to be influenced by developmental changes from adolescence to late adulthood. The aim of this study is to uncover these neural correlates during a slot machine gambling task across the lifespan. Therefore, we used functional magnetic resonance imaging to investigate 102 volunteers in three different age groups: 34 adolescents, 34 younger adults, and 34 older adults. We focused on the core reward areas ventral striatum (VS) and ventromedial prefrontal cortex (VMPFC), the valence processing associated areas, anterior cingulate cortex (ACC) and insula, as well as information integration associated areas, dorsolateral prefrontal cortex (DLPFC), and inferior parietal lobule (IPL). Results showed that VS and VMPFC were characterized by a hyperactivation in adolescents compared with younger adults. Furthermore, the ACC and insula were characterized by a U-shape pattern (hypoactivation in younger adults compared with adolescents and older adults), whereas the DLPFC and IPL were characterized by a J-shaped form (hyperactivation in older adults compared with younger groups). Furthermore, a functional connectivity analysis revealed an elevated negative functional coupling between the inhibition-related area rIFG and VS in younger adults compared with adolescents. Results indicate that lifespan-related changes during reward anticipation are characterized by different trajectories in different reward network modules and support the hypothesis of an imbalance in maturation of striatal and prefrontal cortex in adolescents. Furthermore, these results suggest compensatory age-specific effects in fronto-parietal regions. Hum Brain Mapp 35:5153-5165, 2014. (c) 2014 Wiley Periodicals, Inc.
Normal aging is associated with a decline in different cognitive domains and local structural atrophy as well as decreases in dopamine concentration and receptor density. To date, it is largely unknown how these reductions in dopaminergic neurotransmission affect human brain regions responsible for reward-based decision making in older adults. Using a learning criterion in a probabilistic object reversal task, we found a learning stage by age interaction in the dorsolateral prefrontal cortex (dIPFC) during decision making. While young adults recruited the dlPFC in an early stage of learning reward associations, older adults recruited the dlPFC when reward associations had already been learned. Furthermore, we found a reduced change in ventral striatal BOLD signal in older as compared to younger adults in response to high probability rewards. Our data are in line with behavioral evidence that older adults show altered stimulus-reward learning and support the view of an altered fronto-striatal interaction during reward-based decision making in old age, which contributes to prolonged learning of reward associations.
Seit etwa zwei Jahrzehnten stellt die kognitive und neuronale Verarbeitung von Nomen und Verben einen bedeutsamen Forschungsschwerpunkt im Bereich der Neurolinguistik und Neuropsychologie dar. Intensive Forschungsbemühungen der letzten Jahre erbrachten eine Reihe von Ergebnissen, die jedoch überwiegend inkonsistent und widersprüchlich sind. Eine häufig vertretene Annahme im Bezug auf die neuronale Basis der Nomen und Verb Verarbeitung ist die so genannte anterior-posterior Dissoziation. Demnach werden Nomen in temporalen und Verben in frontalen Regionen der sprachdominanten, linken Hemisphäre verarbeitet. Die vorliegende Dissertation untersucht mit Hilfe der funktionellen Magnetresonanztomographie, welche kortikalen Regionen in den Abruf von Nomen und Verben beim stillen Bildbennen involviert sind. Ferner wird der Einfluss des Faktors age-of-acquisition (Erwerbsalter) auf die Hirnaktivierung beim Bildbenennen überprüft. Die Ergebnisse der Studie zeigen, dass der Abruf von Nomen und Verben ähnliche kortikale Aktivierungen in bilateral okzipitalen sowie links frontalen, temporalen und inferior parietalen Regionen hervorruft, wobei für Verben stärkere Aktivierungen in links frontalen und bilateral temporalen Arealen beobachtet wurden. Dieses Ergebnis widerspricht der Annahme einer anterior-posterior Dissoziation. Die beobachteten Aktivierungsmuster unterstützen dagegen die Auffassung, dass ein gemeinsames Netzwerk bestehend aus anterioren und posterioren Komponenten für die Verarbeitung von Nomen und Verben beim Bildbenennen verantwortlich ist. Die Studie ergab ferner, dass kortikale Aktivierungen beim Bildbenennen durch das Erwerbsalter moduliert werden. Dabei zeigten sich Aktivierungen für später erworbene Wörter im linken inferioren Frontallappen und im basal temporalen Sprachareal. Die Ergebnisse werden diskutiert und interpretiert vor dem Hintergrund aktueller kognitiver und neuroanatomischer Modelle der Sprachverarbeitung.
fMRI studies of reward find increased neural activity in ventral striatum and medial prefrontal cortex (mPFC), whereas other regions, including the dorsolateral prefrontal cortex (d1PFC), anterior cingulate cortex (ACC), and anterior insula, are activated when anticipating aversive exposure. Although these data suggest differential activation during anticipation of pleasant or of unpleasant exposure, they also arise in the context of different paradigms (e.g., preparation for reward vs. threat of shock) and participants. To determine overlapping and unique regions active during emotional anticipation, we compared neural activity during anticipation of pleasant or unpleasant exposure in the same participants. Cues signalled the upcoming presentation of erotic/romantic, violent, or everyday pictures while BOLD activity during the 9-s anticipatory period was measured using fMRI. Ventral striatum and a ventral mPFC subregion were activated when anticipating pleasant, but not unpleasant or neutral, pictures, whereas activation in other regions was enhanced when anticipating appetitive or aversive scenes.